This proposal, combining established biomedical engineering and clinical expertise from two institutions, seeks to develop and validate a portable, spatially-modulated imaging system with the long term goal of intra-operatively assessing surgical excision margin status for involvement by cancer. A national reexcision rate of 32-63% for breast cancer reflects the considerable clinical impact of a positive resection margin after lumpectomy and the inadequacy of current methods to evaluate specimen margin status intraoperatively. If a surgeon can use this imaging technology to evaluate the presence of residual cancer at a resection margin, then s/he will be able to take directed, additional tissue at the time of the original excision rather than at a separate re-excision procedure. The imaging system we have proposed would remedy the current clinical inadequacies and significantly benefit the patient in reducing surgical risk, costs, recovery time, tumor recurrence rates, psychological stress and a suboptimal cosmetic outcome. This unique imaging technology, ideally suited for quantitative scatter-based imaging in bulk tissue samples, will exploit the recent exciting observation that there are significant differences in benign-associated stromal scatter as compared to tumor-associated stromal scatter in breast cancers. After constructing the modulated imaging system and testing with phantoms for accuracy and repeatability, we hope to demonstrate that the imaging system can differentially quantify scatter in the benign tissue types represented in reduction mammoplasty specimens as validated by the gold standard clinical pathologic diagnosis. We then propose to compare the imaging signatures of lumpectomy specimens performed for breast cancer to the gold standard clinical pathologic diagnosis, and demonstrate a significant difference in the image signature of tumor-associated stroma (invasive and noninvasive carcinoma) in contrast to the surrounding benign breast tissue. Unlike many new biotechnologies, the development of this imaging system seeks to enhance, rather than replace, current gold-standard diagnostic techniques. The imaging system is not expected to be 100% accurate and the false negative rate of the procedure/technique does not have to approach zero to become clinically useful/significant because patients with resection margins which are later determined to be falsely negative, by comparison with the usual standard-of-care pathology assessment, will require a re-excision which is no different than current practice. However, a cost/benefit analysis that demonstrates a reduction in the institutional re-excision rate would justify the formal evaluation of the imaging system, in the intra-operative assessment of margin involvement by cancer, in a future prospective clinical trial. Public Health Relevance Statement: Nationwide today, up to 63% of women undergoing breast-conserving lumpectomy surgery for breast cancer will require at least one separate re-excision procedure to ensure that their surgical resection margins are uninvolved by tumor. An imaging technology, available in the operating room, with the potential of directing the surgeons to re-excise a positive resection margin at the time of that first lumpectomy procedure, would have a major impact on the health care system in reducing repeat surgery risk, costs, recovery time, tumor recurrence rates, psychological stress to the patient and a suboptimal cosmetic result.